The goal of this project is to elucidate the mechanisms by which nerve cells degenerate in Parkinson's disease and other neurodegenerative disorders. Clinically, these central nervous system diseases are characterized by progressive decline in neurologic function and chronic disability. Pathologically, intracellular inclusions containing specific proteins are found in susceptible neuronal populations. In Parkinson's disease, for example, mutations in the synaptic protein alpha-synuclein are associated with rare autosomal dominant forms of the disease, and alpha-synuclein is an abundant component of Lewy bodies in sporadic Parkinson's disease as well. We have found that alpha-synuclein, which is ubiquitinated and processed via the proteasome system, is degraded at a slower rate when mutated compared with the wild-type protein, thus, making the mutant protein more prone to accumulation and aggregation in the cell. We also found that these disease-causing mutations enhance the vulnerability of dopaminergic neurons to reactive oxygen species generators. Mounting evidence point to oxidative stress in the microenvironment of the substantia nigra pars compacta which bears the brunt of the Parkinson pathology. The presence of mutant alpha-synuclein, therefore, can accelerate free radical induced death of dopaminergic neurons.Another group of neurodegenerative diseases characterized by intracellular inclusions is triplet repeat expansion disorders. We had found that polyglutamine tract-binding protein 1 (PQBP-1) interacts with triplet repeat disease gene products such as huntingtin and ataxin-1, and binds with an even higher affinity to their respective expanded isoforms. To gain insight into the role of PQBP-1 in cellular homeostasis and death, we searched for its other interacting partner(s) and found U5 snRNP-specific protein (U5-15kD), the yeast homolog of which is involved in cell cycle progression and pre-mRNA splicing. As expected, human U5-15kD also binds to poly(rG). These results collectively suggest that PQBP-1 and U5-15kD are associated proteins and that this complex may function as a component of the mRNA splicing machinery.